Several publications and patent documents are referenced in this application in order to more fully describe the state of the art to which this invention pertains. The disclosure of each of these publications and documents is incorporated by reference herein.
The control of viral infection in HIV-1 positive individuals requires the function of the innate and adaptive arms of the immune system (1, 2). While the induction of antigen specific cytotoxic T lymphocytes (CTL) involved in direct killing of HIV infected cells is the function of the adaptive immune response, the innate immune system is part of the primary defense against pathogenic attack and allows the development of a specific adaptive response (3). CD8+ cells derived from HIV-1 positive and negative donors are thought to contribute to the innate defense as they secrete soluble molecules that inhibit HIV-1 replication in vitro (4-7).
The β chemokines, RANTES, MIP-1α and MIP-1β are active components found in CD8+ cell supernatants that inhibit entry of R5 strains of HIV-1 (8). Another chemokine, macrophage-derived cytokine (MDC), also isolated from CD8+ cell supernantants was reported to have activity against R5 and X4 strains of HIV-1, although synthetic forms have more restricted inhibitory activity (9-11) which may be due to necessary processing (11). The CXCR4 ligand, stromal-derived factor (SDF1) blocks entry of X4 viruses but is not produced by CD8+ cells (12, 13). IL-16, as well as interferon-α, β, and γ can all be found in variable amounts in CD8+ cell supernatants and exhibit anti-HIV activity, as does the amino terminal fragment of urokinase-type plasminogen activator (uPA) (14-17) and a form of antithrombin III. A number of groups, have shown that the anti-HIV-1 activity found in CD8+ cell supernatants is not fully accounted for by β chemokines, II-16 or the interferons (4, 18, 19).
In view of the epidemic of diseases caused by HIV-1 infection, there is a need to identify novel preventative and therapeutic agents that can be used to combat HIV-1 transmission and progression of HIV-1 infection and related diseases. As indicated herein above, CD8+ cell supernatants offer a potential source for such preventative and therapeutic agents.